Gulf War Veterans' Illnesses (GWVI) profoundly influence quality of life and functional outcome in many Veterans with a history of deployment to the Persian Gulf Theater. Although elucidation of the precise physiological underpinnings of these complex symptom constellations remain a focus of ongoing scientific inquiry, it is clear that multi-system involvement is one of the hallmarks of GWVI. There is currently a dearth of randomized controlled trials (RCTs) investigating GWVI, and effective new interventions are urgently needed to enhance functional outcomes in Gulf War Veterans and to effectively treat persistent chronic symptoms spanning multiple clinical domains - including pain symptoms, cognitive symptoms, fatigue, and global psychological symptoms. An optimal pharmacological intervention would potentially target all of these functional and clinical domains. The identification of biomarkers for the prediction of therapeutic response to the intervention would also be critical. In addition, a rapid trajectory to therapeutic development and dissemination would be ideal. Compelling preclinical and clinical data suggest that neurosteroid interventions may potentially meet all of these important criteria. Neurosteroids are endogenous molecules that are enriched in human brain and synthesized de novo from cholesterol in the central nervous system (CNS). Neurosteroids have pleiotropic actions that are potentially relevant to multiple functional and clinical domains in GWVI - including analgesic actions, anti-inflammatory effects, enhancement of learning and memory in rodent models (and associations with cognitive improvements in pilot clinical studies), neurotrophic and antidepressant properties, neurogenesis-promoting effects, and pronounced neuroprotective actions. Because neurosteroids such as pregnenolone are available over-the-counter as dietary supplements in the United States, their translation to clinical therapeutics is potentially very rapid. For example, we have conducted pilot RCTs in Veteran cohorts and hold FDA Investigational New Drug numbers for the use of neurosteroids in traumatic brain injury [TBI] (FDA IND #78,270) and psychotic disorders (FDA IND #71,768). Our preliminary data also support the possibility that neurosteroids may be predictors of therapeutic response. We thus hypothesize that a neurosteroid intervention with pleiotropic actions could be advantageous for the diverse clinical manifestations in GWVI. We therefore propose an RCT with a neurosteroid intervention in Gulf War Veterans with a history of deployment and symptoms of GWVI. We also propose to conduct neurosteroid biomarker investigations by mass spectrometry to characterize the metabolic profile of pregnenolone, to obtain valuable pharmacokinetic data, and to identify possible windows of optimal therapeutic efficacy and potential neurosteroid predictors of clinical response. Specific Aim 1: To conduct an RCT with the neurosteroid pregnenolone in 140 Gulf War Veterans with GWVI and a history of deployment (70 Veterans randomized to adjunctive pregnenolone, 70 Veterans randomized to placebo), targeting functional outcome as the primary endpoint as assessed by the SF-36. Based on our preliminary data with neurosteroid interventions, secondary endpoints will be pain symptoms, cognitive symptoms, fatigue, and global psychological functioning. Specific Aim 2: To conduct candidate biomarker investigations quantifying pregnenolone and pregnenolone metabolite levels (allopregnanolone, pregnanolone, androsterone, others) at baseline, during treatment, and post-treatment with pregnenolone using mass spectrometry-based methodologies in order to: a.) characterize the pharmacokinetics of pregnenolone and its metabolic profile - which could yield valuable dosing information and identify pharmacological windows of optimal therapeutic efficacy, and b.) identify potential neurosteroid predictors of therapeutic response, which could lead to the development of new neurosteroid interventional strategies that build on the current investigation and exhibit promise as pharmacological candidates in GWVI.